The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification
Abstract
The genetic analysis of congenital skull malformations provides insight into normal mechanisms of calvarial osteogenesis. Enlarged parietal foramina (PFM) are oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. PFM are usually asymptomatic, but may be associated with headache, scalp defects and structural or vascular malformations of the brain. Inheritance is frequently autosomal dominant, but no causative mutations have been identified in non-syndromic cases. We describe here heterozygous mutations of the homeobox gene MSX2 (located on 5q34-q35) in three unrelated families with PFM. One is a deletion of approximately 206 kb including the entire gene and the others are intragenic mutations of the DNA-binding homeodomain (RK159-160del and R172H) that predict disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal Msx2 DNA-binding site. Our findings contrast with the only described MSX2 homeodomain mutation (P148H), associated with craniosynostosis, that binds with enhanced affinity to the same target. This demonstrates that MSX2 dosage is critical for human skull development and suggests that PFM and craniosynostosis result, respectively, from loss and gain of activity in an MSX2-mediated pathway of calvarial osteogenic differentiation.
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“Functional haploinsufficiency of MSX2 causes parietal foramina (PFM), and whole-body Msx2 knockout mice exhibit pleiotropic defects in bone mass and ectodermal organ formation22,23.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [23]
In the citing paper
“MSX2 mutations cause Boston-type craniosynostosis, and haploinsufficiency of human MSX2 causes deficient ossification around the parietal notch23.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [23]
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Metadata
- Authors
- Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., & Maxson, R. E.
- Affiliations
- John Radcliffe Hospital (GB)
- University of Southern California (US)
- Churchill Hospital (GB)
- Corresponding author
- Wilkie, Andrew O.M.
- Venue
- Nature Genetics
- Published
- 2000-04
- Volume
- 24
- Issue
- 4
- Pages
- 387-390
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1489648704
- Cited by
- 315
- References
- 31
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 10 · 2023: 1 · 2022: 3 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 11 · 2015: 7 · 2014: 9 · 2013: 14 · 2012: 17
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Craniofacial Disorders and Treatments
- Health Sciences › Dentistry › General Dentistry › dental development and anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- Msx2, homeobox genes, haploinsufficiency, parietal foramina, skull ossification, craniosynostosis, homeodomain mutations, congenital skull malformation, autosomal dominant inheritance, gene dosage
- MeSH terms
- Adult, Animals, Base Sequence, Child, Child, Preschool, Chromosomes, Human, Pair 5, Cranial Sutures, DNA Mutational Analysis, DNA-Binding Proteins, Female, Humans, Infant, Male, Molecular Sequence Data, Mutation, Osteogenesis, Parietal Bone, Pedigree, Radiography, Skull, Blotting, Southern, Sequence Deletion, Homeodomain Proteins, Microsatellite Repeats, Mice
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